NitroMed Ties Gene Biomarkers to BiDil Benefit

ByKevin Davies

April 14, 2006 | The FDA approval last year of BiDil, the heart failure drug for blacks, raised howls of controversy. Critics panned the drug as the world’s first “ethnic medicine,” and its producer, NitroMed, and the FDA for essentially using skin color as a surrogate marker for heart disease. (See The Race Prescription Card, Jan. 2005 Bio-IT World, p. 4.)

At the annual meeting of the American College of Cardiology (ACC) in Atlanta in March, researchers presented two papers that offer the first preliminary hints of genetic factors that affect BiDil response.

“We don’t believe one gene is a determinant of heart failure, or two or three,” says Michael Sabolinski, NitroMed’s chief medical officer. “But we can lean a bit about which subpopulation...is most responsive.” He added: “This would be the future of personalized medicine. We want to be able to define patients who best respond to BiDil, first with the African-American population, but also among whites [with] a lower frequency.”

The data presented at ACC were gathered in collaboration with the team of Dennis McNamara, director of the Heart Failure/Transplantation Program at the University of Pittsburgh Medical Center. NitroMed enrolled 360 of the 1,050 self-identified black patients who participated in the original African American Heart Failure Trial (A-HeFT) trial, in a new study called the “Genetic Risk Assessment in Heart Failure (GRAHF).”

The study looked at specific variations in two candidate genes — aldosterone synthase and beta-1 adrenergic receptor. The frequency of genotypes important for cardiovascular diseases were determined amongst black patients in GRAHF compared with white heart failure subjects.

The investigators examined the prevalence among different races of a (C/T) SNP in the promoter (position -344) of the aldosterone synthase gene. The -344 C variant is associated with increased aldosterone production, which in turn leads to elevated blood pressure.

In the GRAHF study, 62 percent of black patients with heart failure had a TT genotype at -344. By contrast, only one-third of white patients with heart failure were TT homozygotes. The preliminary data suggest that the T SNP may auger well for BiDil response. Sabolinski explains: “If you look at the TT subset, the score for BiDil was highly significantly superior to the placebo group. Also true of the quality of life. BiDil worked better for the TT genotype. When we [group] the TC and CC genotypes together, there are no statistically significant results.”

A second analysis from GRAHF studied the Glycine389Arginine polymorphism in the beta-1 adrenergic receptor, which regulates heart rhythm. “The data are tantalizing,” says Sabolinski. “We truly are not trying to hang the whole story on aldosterone synthase or beta adrenergic receptor.”

Although NitroMed executives have acknowledged a disappointing initial reception to the drug, Sabolinski insists: “I think every African-American patient with heart failure will show improvement with BiDil. It should be the new standard of care.”